Discovery, Optimization, and Preclinical Pharmacology of EP652, a METTL3 Inhibitor with Efficacy in Liquid and Solid Tumor Models

METTL3 is the RNA methyltransferase predominantly responsible
for
the addition of N6-methyladenosine (m6A), the
most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the
appearance and progression of acute myeloid leukemia (AML), thereby
making METTL3 an attractive target for cancer therapeutics. We report
herein the discovery and optimization of small-molecule inhibitors
of METTL3, culminating in the selection of EP652 as an in vivo proof-of-concept compound. EP652 potently
inhibits the enzymatic activity of METTL3, has favorable PK parameters,
and demonstrates efficacy in preclinical oncology models, indicating
that pharmacological inhibition of METTL3 is a viable strategy for
the treatment of liquid and solid tumors.